Clozapine (trade names Clozaril®;
Leponex®), approved by the FDA in 1989, was the first of the atypical
antipsychotics. Clozapine is the only FDA approved medication indicated for
treatment-resistant schizophrenia and for reducing the risk of suicidal behaviour
in patients with schizophrenia.

History

Clozapine was developed by Sandoz in 1961, and
introduced in Europe ten years later. In 1975, after reports of agranulocytosis
leading to death in some clozapine-treated patients, clozapine was voluntarily
withdrawn by the manufacturer. Clozapine fell out of favor for more than
a decade. However, when studies demonstrated that clozapine was more effective
against treatment-resistant schizophrenia than other antipsychotics, the
FDA approved its use only for treatment-resistant schizophrenia, and required
regular haematological monitoring to detect granulocytopenia, before
agranulocytosis develops. In December of 2002, clozapine was also approved
for reducing the risk of suicide in schizophrenic or schizoaffective patients
judged to be at chronic risk for suicidal behavior.

Chemistry

Clozapine is yellow crystalline solid with melting
point 183-184 °C. It is insoluble in water, soluble in acetone, very
well soluble in chloroform. Chemical name is
8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine,
C18H19ClN4.

Pharmacology

The effectiveness of clozapine as an antipsychotic
is thought to be mediated by antagonism at dopamine receptors. Compared to
typical antipsychotics, with their strong affinity for D2 receptors, clozapine
has a relatively low affinity (about 100X less than haloperidol) for the
D2 receptor subtype, and this difference in affinity (more specifically the
fast dissociation constant that results in lower affinity) is theorized to
be responsible for the "atypicality" of clozapine. Clozapine also displays
antagonism at 5-HT2, alpha adrenergic, H1, and cholinergic receptors. The
role of antagonism of these neurotransmitter systems is clinical profile
of clozapine is unknown, however serotonergic antagonism may play a contributing
role in the "atypicality" of this antipsychotic. Alpha adrenergic, histaminic
and cholinergic antagonism may play contribute to the side effect profile
of clozapine.

Pharmacokinetics

The elimination half-life of clozapine is about
12 hours. The time to peak concentration after oral dosing is about 2.5 hours,
and food does not appear to effect the bioavailability of clozapine. Clozapine
is extensively hepatically metabolized and eliminated in the urine and
feces.

Metabolism

Clozapine is metabolize via the cytochrome P450
system in humans to polar metabolites suitable for elimination. The cytochrome
P450 isoenzyme 1A2 is primarily responsible for clozapine metabolism, but
2C, 2D6, 2E1 and 3A3/4 appear to play roles as well. Agents which induce
(e.g. cigarette smoke) or inhibit (e.g. theophylline, ciprofloxacin) CYP1A2
may increase or decrease, respectively, the metabolism of clozapine.

Contraindications

Clozapine is contraindicated in individuals with
uncontrolled epilepsy, myeloproliferative disease, or agranulocytosis with
prior clozapine treatment.

Side effects

Clozapine carries a black box warning for drug
induced agranulocytosis. Agranulocytosis occurs in about 1% of patients who
take clozapine during the first 6 months of treatment, and decreases to about
0.01% thereafter. Patients who have experienced agranulocytosis with prior
treatment of clozapine should not receive clozapine again. Clozapine also
carries black box warnings for seizures, myocarditis, and "other adverse
cardiovascular and respiratory effects."

Lowering of the seizure threshold may be dose
related and slow initial titration of dose may decrease the risk for
precipitating seizures. Slow titration of dosing may also decrease the risk
for orthostasis and other adverse cardiovascular side effects. Common side
effects with clozapine treatment include: constipation, drooling,
muscle-stiffness, sedation, tremors, orthostasis,hyperglycemia and weight-gain.
The risks of extrapyramidal symptoms and tardive dyskinesias are much less
with clozapine when compared to the typical antipsychotics (also known as
conventional antipsychotics or conventional neuroleptics).

Recently the FDA required the manufacturers of
all atypical antipsychotics to include a warning about the risk of hyperglycemia
and diabetes with atypical antipsychotics. Indeed, there are case reports
of clozapine-induced hyperglycemia and diabetes. Additionally there are case
reports of clozapine-induced diabetic ketoacidosis. There is data showing
that clozapine can decrease insulin sensitivity. Clozapine should be used
with caution in patients who are diagnosed with diabetes or in patients at
risk for developing diabetes. All patients receiving clozapine should have
their fasting blood glucose monitored.

In addition to hyperglycemia, weight gain may
be experienced by patients treated with clozapine. Impaired glucose metabolism
and obesity have been shown to be constituents of the metabolic syndrome
and may increase the risk of cardiovascular disease. The data suggests that
clozapine may be more likely to cause adverse metabolic effects than some
of the other atypical antipsychotics. Research has indicated that clozapine
may cause a deficiency of selenium.

Monitoring

Patient's who take clozapine are advised to have
a blood cell count every week, for the first 6 months of therapy. After this
they should continue to conduct said count every 2 weeks. If the number of
white blood-cells drops notably, one should consult with a hematologist.
If you are using clozapine and have a sore throat, or fever, then you should
inform your doctor.

More recently, a regular echocardiogram is also
recommended to detect myocarditis.

The manufacturers of both the brand and generic
clozapine are required by the FDA to track white blood cells counts for patients
receiving clozapine, and pharmacies are required to obtain a copy of the
CBC prior to dispensing the medication to the patient. The purpose of the
monitoring system is to prevent rechallenge with clozapine in patients with
a history of clozapine-induced agranulocytosis and to detect leukopenic events
among patients taking clozapine.

The information above is not intended
for and should not be used as a substitute for the diagnosis and/or treatment
by a licensed, qualified, health-care professional. This article is licensed
under the GNU Free Documentation
License. It incorporates material originating from the Wikipedia article
"Clozapine".